MET Inhibitor Increases Osimertinib Activity in EGFR+ Advanced NSCLC

Adding a mutation-specific targeted drug to osimertinib (Tagrisso) substantially increased the objective response rate (ORR) in newly diagnosed EGFR-mutant, MET-aberrant non-small cell lung cancer (NSCLC), a small randomized trial showed.

ORR increased from 60.9% with osimertinib alone to 90.5% with the addition of the MET-selective tyrosine kinase inhibitor (TKI) savolitinib. The disease control rate increased from 87.0% with osimertinib monotherapy to 95.2% with the combination.

Grade ≥3 treatment-emergent adverse events (TEAEs) also increased substantially with the combination, and a fourth of patients discontinued treatment because of AEs, reported Jin-Ji Yang, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, at the World Conference on Lung Cancer.

“Combination therapy with osimertinib and savolitinib demonstrated clinically meaningful improvement in the primary endpoint,” said Yang.

“Immature progression-free survival [PFS] data also showed a positive trend in favor of the combination therapy. The safety profiles of osimertinib monotherapy and osimertinib plus savolitinib were as expected, tolerated, and manageable,” Yang added.

“This combination regimen has the potential to provide a novel first-line treatment option for such patients [with EGFR-mutant, MET-aberrant NSCLC].”

The FLOWERS trial that Yang reported explored the role of mostly MET protein overexpression in untreated EGFR-positive lung cancer patients, said invited discussant Paul Paik, MD, of Memorial Sloan Kettering Cancer Center in New York City. The study added to existing data suggesting that high MET expression is a marker or predictor of poor prognosis and that outcomes are improved by MET inhibition.

“There is in the first-line setting a quality-of-life/side effects tradeoff,” said Paik. “This is a theme as newer drugs and combinations get approved. I would also argue that we need some kind of internal control for the biomarker performance, since it is a little bit uncertain. [The study] would benefit from a cohort, for example, that was MET-negative or MET-low and EGFR-positive, treated at least with savolitinib, if not with osimertinib.”

“There is some serial [circulating tumor] DNA and formal [acquired resistance] testing that is going to happen in this study. That would be interesting to try to get at issues of clonality that might be present and also to better characterize MET as a co-driver in this setting.”

Limited data suggest MET-amplification/overexpression occurs infrequently in EGFR-mutated advanced NSCLC, estimated at 2-5% and 11-15% respectively of cases, Yang noted in his introduction. Preclinical studies have shown that co-occurrence of EGFR mutations and MET aberrations reduces tumor sensitivity to EGFR inhibitors, potentially a key mechanism of primary resistance to first-line TKI monotherapy.

Some clinical studies have shown that patients with advanced EGFR-mutated NSCLC with MET aberrations have poor clinical outcomes following first-line treatment with EGFR TKIs. In preclinical testing, the combination of osimertinib and savolitinib demonstrated potent anti-tumor activity, suggesting a potentially promising first-line therapy for such patients, Yang continued.

Investigators in the FLOWERS trial enrolled patients with untreated advanced EGFR+/MET-aberrant NSCLC. MET overexpression was defined as IHC 3+ in ≥75% of tumor cells and MET amplification as determined by fluorescence in-situ hybridization or next-generation sequencing. Patients were randomized to osimertinib monotherapy or osimertinib with the addition of savolitinib. The primary endpoint was ORR.

Data analysis included 44 patients. The primary analysis showed that 60.9% of patients achieved partial responses with osimertinib alone, increasing to 90.5% with the addition of savolitinib. An additional 26.1% of patients treated with single-agent osimertinib and 4.8% of those treated with the combination had stable disease. Single-agent osimertinib and the combination demonstrated activity in tumors with MET overexpression, MET amplification, or both.

The study population had a median follow-up of 8.2 months. Median best reduction in tumor size was similar with osimertinib (42.2%) and the combination (47.7%). Median duration of response was 8.4 months with osimertinib versus 18.6 months with the addition of savolitinib.

Patients randomized to combination therapy had more than a twofold improvement in median progression-free survival (PFS, 19.6 vs 9.3 months), representing a 41% reduction in the hazard ratio. The 6-month PFS was 87.3% with savolitinib and 82.1% with single-agent osimertinib. Analysis of 12-month PFS showed a larger difference, 65.5% versus 49.0%.

Grade ≥3 TEAEs occurred in 8.7% of the osimertinib arm and 57.1% of patients randomized to the combination. No patient randomized to single-agent osimertinib discontinued treatment because of TEAEs, as compared with 23.8% of patients in the combination arm.

The most common TEAEs with osimertinib were diarrhea, rash, and pruritus, whereas rash, thrombocytopenia, peripheral edema, and an increase in liver function tests were most frequent in the combination arm. No fatal adverse events occurred in either group.

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